EP0543892B1 - N-(mercaptoakyl)urees et carbamates - Google Patents

N-(mercaptoakyl)urees et carbamates Download PDF

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EP0543892B1
EP0543892B1 EP91914916A EP91914916A EP0543892B1 EP 0543892 B1 EP0543892 B1 EP 0543892B1 EP 91914916 A EP91914916 A EP 91914916A EP 91914916 A EP91914916 A EP 91914916A EP 0543892 B1 EP0543892 B1 EP 0543892B1
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compound
formula
lower alkyl
mercaptoalkyl
aryl
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EP0543892A1 (fr
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Bernard R. Neustadt
Alan Bronnenkant
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Merck Sharp and Dohme Corp
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Schering Corp
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C333/00—Derivatives of thiocarbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C333/02—Monothiocarbamic acids; Derivatives thereof
    • C07C333/04—Monothiocarbamic acids; Derivatives thereof having nitrogen atoms of thiocarbamic groups bound to hydrogen atoms or to acyclic carbon atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P15/00—Drugs for genital or sexual disorders; Contraceptives
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P21/00—Drugs for disorders of the muscular or neuromuscular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/43—Y being a hetero atom
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C323/00—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups
    • C07C323/23—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton
    • C07C323/39—Thiols, sulfides, hydropolysulfides or polysulfides substituted by halogen, oxygen or nitrogen atoms, or by sulfur atoms not being part of thio groups containing thio groups and nitrogen atoms, not being part of nitro or nitroso groups, bound to the same carbon skeleton at least one of the nitrogen atoms being part of any of the groups, X being a hetero atom, Y being any atom
    • C07C323/43—Y being a hetero atom
    • C07C323/44—X or Y being nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C327/00—Thiocarboxylic acids
    • C07C327/20—Esters of monothiocarboxylic acids
    • C07C327/30—Esters of monothiocarboxylic acids having sulfur atoms of esterified thiocarboxyl groups bound to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms, not being part of nitro or nitroso groups

Definitions

  • the present invention relates to novel N-(mercaptoalkyl)ureas and carbamates useful in the treatment of cardiovascular disorders and pain conditions.
  • Cardiovascular disorders which may be treated with compounds of the present invention include hypertension, congestive heart failure, edema and renal insufficiency.
  • Human hypertension represents a disease of multiple etiologies. Included among these is a sodium and volume dependent low renin form of hypertension. Drugs that act to control one aspect of hypertension will not necessarily be effective in controlling another.
  • Enkephalin is a natural opiate receptor agonist which is known to produce a profound analgesia when injected into the brain ventricle of rats. It is also known in the art that enkephalin is acted upon by a group of enzymes known generically as enkephalinases, which are also naturally occurring, and is inactivated thereby.
  • enkephalinase inhibitors useful as analgesics and in the treatment of hypertension.
  • U.S. 4,774,256 discloses compounds of the formula wherein n is 1-15 and R2 and R3 are various aryl, arylalkyl and heteroarylalkyl groups. The compounds are disclosed as having enkephalinase inhibiting activity.
  • U.S. 4,801,609 to Haslanger et al discloses antihypertensive compounds of the formula wherein n is 0 or 1; R1 is substituted phenyl and R2 is substituted alkyl, phenyl or heteroaryl.
  • European Patent Application 161,769 discloses enkephalinase inhibitors of the formula wherein R2 includes alkyl, aryl and arylalkyl, R3 includes alkyl, aryl, heteroaryl, arylalkyl and heteroarylalkyl, and n is 1-15.
  • Atrial natriuretic factors ANF which help to regulate blood pressure, blood volume and the excretion of water, sodium and potassium.
  • ANF atrial natriuretic factors
  • ANF were found to produce a short-term reduction in blood pressure and to be useful in the treatment of congestive heart failure. See P. Needleman et al, "Atriopeptin: A Cardiac Hormone Intimately Involved in Fluid, Electrolyte and Blood-Pressure Homeostasis", N. Engl. J. Med. , 314 , 13 (1986) pp. 828-834, and M.
  • ACE inhibitors which compounds are useful in blocking the rise in blood pressure caused by increases in vascular resistance and fluid volume due to the formation of angiotensin II from angiotensin I.
  • ACE inhibitors see M. Wyvratt and A. Patchett, "Recent Developments in the Design of Angiotensin Converting Enzyme Inhibitors" in Med. Res. Rev. Vol. 5, No. 4 (1985) pp. 483-531.
  • Novel compounds of the present invention are represented by the formulae wherein A is a monocyclic or bicyclic arylene or heteroarylene; Q is hydrogen or R9CO-; Y is -O-, -S- or -NR8-; R1 is lower alkyl, cyclolower alkyl, aryl or heteroaryl; R2 and R8 are independently hydrogen; lower alkyl; cyclolower alkyl; lower alkyl substituted with hydroxy, lower alkoxy, mercapto, lower alkylthio, aryl or heteroaryl; aryl; or heteroaryl; R3 is -OR5 or -NR5R6; R4 is -(CH2) q R7; or R2 and R4 together with the carbons to which they are attached complete a 5-, 6- or 7-membered carbocyclic ring; R5 and R6 are independently selected from the group consisting of hydrogen, lower alkyl, hydroxy lower alkyl, lower alkoxy-lower alkyl
  • a preferred group of compounds of formula I of the present invention is that wherein p is zero. Also preferred compounds of formula I are those wherein p is zero and n is zero or 1.
  • a third preferred group of compounds is that wherein Y is -O- or -NR8-. Still another preferred group of compounds of formula I is that wherein R2 is hydrogen.
  • R8 is preferably hydrogen or phenyl.
  • a preferred group of compounds of formula II is that wherein A is phenylene. Also preferred are compounds of formula II wherein Y is -O- or -NH-.
  • preferred values for Q are hydrogen and acyl.
  • Other preferred compounds of formula I and II are those wherein R1 is phenyl or lower alkyl-substituted phenyl, for example tolyl.
  • Yet another preferred group of compounds is that wherein R3 is hydroxy, lower alkoxy or aryl lower alkoxy.
  • a preferred value for m is 1.
  • Y is -O- or -NR8- wherein R8 is hydrogen or phenyl; R1 is phenyl or tolyl; m is 1; R2 is hydrogen; p is 0; and R3 is hydroxy or lower alkoxy.
  • Especially preferred compounds of formula II are those wherein Y is -O- or -NH-, R1 is phenyl or tolyl, m is 1, A is phenylene and R3 is hydroxy or alkoxy.
  • the invention also relates to the treatment of cardiovascular diseases with a combination of an N-(mercaptoalkyl)urea or carbamate of the present invention and an atrial natriuretic factor (ANF) and with a combination of an N-(mercaptoalkyl)urea or carbamate of the present invention and an angiotensin converting enzyme (ACE) inhibitor.
  • ANF atrial natriuretic factor
  • ACE angiotensin converting enzyme
  • compositions comprising an N-(mercaptoalkyl)urea or carbamate of this invention, alone or in combination with an ANF or an ACE inhibitor, and to methods of treatment of cardiovascular diseases comprising administering an N-(mercaptoalkyl)urea or carbamate of this invention, alone or in combination with an ANF or an ACE inhibitor, to a mammal in need of such treatment.
  • Still another aspect of the invention relates to a method of treating pain conditions by administering an N-(mercaptoalkyl)urea or carbamate of this invention, thereby inhibiting the action of enkephalinase in a mammal and eliciting an analgesic effect.
  • Analgesic pharmaceutical compositions comprising said N-(mercaptoalkyl)ureas or carbamates are also contemplated.
  • An additional aspect of the invention relates to a method of treating nephrotoxicity resulting from immunosuppression therapy by administration of an N-(mercaptoalkyl)urea or carbamate of this invention.
  • lower alkyl means straight or branched alkyl chains of 1 to 6 carbon atoms
  • lower alkoxy similarly refers to alkoxy groups having 1 to 6 carbon atoms
  • Cyclolower alkyl means cyclic alkyl groups of 3 to 6 carbon atoms.
  • Aryl means mono-cyclic or fused ring bicyclic carbocyclic aromatic groups having 6 to 10 ring members and "heteroaryl” means mono-cyclic or fused ring bicyclic aromatic groups having 5-10 ring members wherein 1-2 ring members are independently nitrogen, oxygen or sulfur, wherein the carbon ring members of the aryl and heteroaryl groups are substituted by zero to three substituents selected from the group consisting of lower alkyl, hydroxy, halo, lower alkoxy, cyclolower alkyl, cyano, aminomethyl, trifluoromethyl, phenyl, phenoxy or phenylthio.
  • carbocyclic aryl groups are phenyl, ⁇ -naphthyl and ⁇ -naphthyl
  • heterocyclic aryl groups are furyl, thienyl, pyrrolyl, benzofuryl, benzothienyl, indolyl and pyridyl. All positional isomers, e.g. 2-pyridyl, 3-pyridyl, are contemplated.
  • Alkylene means a bivalent chain of methylene groups, e.g., a group of the formula -(CH2) x -, wherein x is 4, 5 or 6.
  • Arylene means a bivalent phenyl group or a fused ring bicyclic carbocyclic aromatic group joined to the molecule by a bivalent phenyl group, e.g. a group of the formula "Heteroarylene” similarly means a bivalent monocyclic or fused ring bicyclic heteroaryl group.
  • Halo refers to fluorine, chlorine, bromine or iodine radicals.
  • Certain compounds of the invention are acidic e.g., those compounds which possess a carboxyl group. These compounds form pharmaceutically acceptable salts with inorganic and organic bases. Examples of such salts are the sodium, potassium, calcium, aluminum, gold and silver salts. Also included are salts formed with pharmaceutically acceptable amines such as ammonia, alkyl amines, hydroxyalkylamines, N-methylglucamine and the like.
  • the salts may be formed by conventional means, as by reacting the free acid form of the product with one or more equivalents of the appropriate base or acid in a solvent or medium in which the salt is insoluble, or in a solvent such as water which is then removed in vacuo or by freeze-drying or by exchanging the cations of an existing salt for another cation on a suitable ion exchange resin.
  • Compounds of formulae I and II have at least one asymmetrical carbon atom and therefore include various stereoisomers.
  • the invention includes all such isomers both in pure form and in admixture, including racemic mixtures.
  • An aspect of the present invention described above relates to the combination of a compound of formulae I or II with an ANF.
  • ANF As indicated by Needleman et al., a number of ANF have been isolated so far, all having the same core sequence of 17 amino acids within a cysteine disulfide bridge, but having different N-termini lengths. These peptides represent N-terminal truncated fragments (21-48 amino acids) of a common preprohormone (151 and 152 amino acids for man and rats, respectively).
  • Human, porcine and bovine carboxy-terminal 28-amino acid peptides are identical and differ from similar peptides in rats and mice in that the former contain a methionine group at position 12 while the latter contain isoleucine.
  • ANFs contemplated for use in this invention are ⁇ human AP 21 (atriopeptin I), ⁇ human AP 28, ⁇ human AP 23 (atriopeptin II or APII), ⁇ human AP 24, ⁇ human AP 25, ⁇ human AP 26, ⁇ human AP 33, and the corresponding rat sequence of each of the above wherein Met 12 is Ile. See Table I for a comparison of the peptides.
  • amino acids are designated by their single-letter abbreviations, namely A Ala Alanine M Met Methionine C Cys Cysteine N Asn Asparagine D Asp Aspartic acid P Pro Proline F Phe Phenylalanine Q Gln Glutamine G Gly Glycine R Arg Arginine I Ile Isoleucine S Ser Serine L Leu Leucine Y Tyr Tyrosine; M* is replaced by I (Ile), in the rat peptide; and the two C ⁇ (Cys) residues are connected by a disulfide bridge.
  • Another aspect of the invention is the administration of a combination of an ACE inhibitor and a compound of formula I or II.
  • ACE inhibitors are those disclosed in the article by Wyvratt et al., cited above.
  • Table II lists ACE inhibitors preferred for use in the combination of this invention.
  • Routes 1 and 2 Two examples of synthetic methods are shown in Routes 1 and 2.
  • acid III is converted into isocyanate IV, for example by reaction with diphenylphosphorylazide at elevated temperatures (e.g. 80°C) in the presence of a base such as triethylamine in a solvent such as toluene.
  • the isocyanate need not be isolated.
  • IV is reacted with an amine, alcohol, or thiol of formula V or VI to obtain compounds of formula I or II, respectively: wherein Q, Y, A, R1, R2, R3, R4, m, n, and p are as defined above.
  • the isocyanate IV is treated with benzyl alcohol to produce the benzyl carbamate, VII.
  • the carbamate VII is then converted to an amine VIII or a reactive derivative thereof, typically an amine salt, for example by treatment with an acid, preferably HBr.
  • the amine or reactive derivative is then reacted with a compound of formula IX or X in an inert solvent such as methylene chloride in the presence of a base such as triethylamine at room temperature to obtain compounds of formula I or II, respectively: wherein Q, A, R1, R2, R3, R4, m, n, and p are as defined above, and wherein Z is -NCO, -N(R8)COCl, or -OC(O)Cl, to obtain compounds wherein Y is -NH-, -NR8-, and -O-, respectively.
  • protecting groups In both routes, the use of suitable protecting groups may be employed.
  • the groups Q and R3 can act as protecting groups.
  • novel compounds of the present invention are effective in treating cardiovascular disorders such as congestive heart failure, edema, renal insufficiency and various types of hypertension, particularly volume expanded hypertension. These novel compounds enhance both the magnitude and duration of the antihypertensive and natriuretic effects of endogenous ANF.
  • Administration of a combination of an N-(mercaptoalkyl)urea or carbamate and an ACE inhibitor provides an antihypertensive and anti-congestive heart failure effect greater than either the N-(mercaptoalkyl)urea or carbamate or ACE inhibitor alone.
  • Administration of a combination of an N-(mercaptoalkyl)urea or carbamate of formula I or II and an exogenous ANF or ACE inhibitor is therefore particularly useful in treating hypertension or congestive heart failure.
  • the present invention therefore also relates to treating cardiovascular disorders with an N-(mercaptoalkyl)urea or carbamate of formula I or II or with an N-(mercaptoalkyl)urea or carbamate of formula I or II in combination with an ANF or an ACE inhibitor, which methods comprise administering to a mammal in need of such treatment an amount of the N-(mercaptoalkyl)urea or carbamate effective to treat hypertension or congestive heart failure or an amount of a combination of an N-(mercaptoalkyl)urea or carbamate and ANF or ACE inhibitor effective to treat hypertension or congestive heart failure.
  • the drug or combination of drugs is preferably administered in a pharmaceutically acceptable carrier, e.g.
  • any convenient combination of dosage forms may be used, e.g. oral N-(mercaptoalkyl)urea or carbamate/oral ANF, oral N-(mercaptoalkyl)urea or carbamate/parenteral ACE inhibitor, parenteral N-(mercaptoalkyl)urea or carbamate/oral ANF, parenteral N-(mercaptoalkyl)urea or carbamate/parenteral ACE inhibitor.
  • N-(mercaptoalkyl)urea or carbamate When the components of a combination of an N-(mercaptoalkyl)urea or carbamate and an ANF are administered separately, it is preferred that the N-(mercaptoalkyl)urea or carbamate be administered first.
  • the present invention also relates to a pharmaceutical composition comprising an N-(mercaptoalkyl)urea or carbamate for use in treating hypertension or congestive heart failure, to a pharmaceutical composition comprising both an N-(mercaptoalkyl)urea or carbamate and an ANF and to a pharmaceutical composition comprising both an N-(mercaptoalkyl)urea or carbamate and an ACE inhibitor.
  • N-(mercaptoalkyl)ureas or carbamates was determined according to the following procedure:
  • mice were dosed subcutaneously (1 ml/kg) with vehicle (methylcellulose, hereinafter MC) or N-(mercaptoalkyl)urea or carbamate and blood pressure was monitored for the next 4 hours.
  • vehicle methylcellulose, hereinafter MC
  • N-(mercaptoalkyl)ureas or carbamates in combination with ANF can be determined according to the following procedures:
  • the animals first undergo a challenge with an ANF such as atriopeptin II (AP II) or AP28 30 ⁇ g/kg iv and at the end of 60 min. are treated with drug vehicle or an N-(mercaptoalkyl)urea or carbamate subcutaneously.
  • a second ANF challenge is administered 15 min. later and blood pressure is monitored for the next 90 min.
  • Animals are prepared for blood pressure measurement as described above. After stabilization, animals are dosed subcutaneously or orally with test drugs or placebo and blood pressure is monitored for the next 4 hr.
  • the compounds having structural formulae I and II have also been found to inhibit the activity of enzymes designated enkephalinases.
  • the compounds are particularly useful for the inhibition of enkephalinase A, which is derived from the striata of both rats and humans.
  • selected compounds having structural formula I and II have been found to inhibit the activity of the aforementioned enzyme. Therefore, the present invention also relates to a method for treating pain by inhibiting the action of enkephalinases in a mammal with a compound of formula I or II, and to analgesic pharmaceutical compositions comprising compounds of formula I or II.
  • Atrial natriuretic peptides in the treatment of nephrotoxicity associated with the immunosuppressive cyclosporin was reported by Capasso et al in the American Journal of Hypertension. 3 , 3 (1990), p. 204-210. Since compounds of this invention enhance endogenous ANF, they can be used alone to treat nephrotoxicity, or they can be administered in combination with exogenous ANF.
  • compositions of this invention comprise an N-(mercaptoalkyl)urea or carbamate, an N-(mercaptoalkyl)urea or carbamate and an ANF or an N-(mercaptoalkyl)urea or carbamate and an ACE inhibitor in combination with a pharmaceutically acceptable carrier for administration to mammals.
  • a pharmaceutically acceptable carrier for administration to mammals.
  • a variety of pharmaceutical forms is suitable, preferably for oral or parenteral administration, although mechanical delivery systems such as transdermal dosage forms are also contemplated.
  • the dally dose of the compound or combinations of this invention for treatment of hypertension or congestive heart failure is as follows: for N-(mercaptoalkyl)ureas or carbamates alone the typical dosage is 0.1 to 10 mg/kg of mammalian weight per day administered in single or divided dosages; for the combination of an N-(mercaptoalkyl)urea or carbamate and an ANF, the typical dosage is 0.1 to 10 mg of N-(mercaptoalkyl)urea or carbamate/ kg mammalian weight per day in single or divided dosages plus 0.001 to 0.1 mg ANF/kg of mammalian weight per day, in single or divided dosages, and for the combination of an N-(mercaptoalkyl)urea or carbamate and an ACE inhibitor, the typical dosage is 0.1 to 10 mg of N-(mercaptoalkyl)urea or carbamate/kg mammalian weight per day in single or divided dosages plus 0.1 to 30 mg ACE inhibitor/kg of mammalian
  • the compounds or combinations of this invention may be administered to patients in a dosage range as follows: for treatment with an N-(mercaptoalkyl)urea or carbamate alone, about 5 to about 500 mg per dose given 1 to 4 times a day, giving a total daily dose of about 5 to 2000 mg per day; for the combination of an N-(mercaptoalkyl)urea or carbamate and ANF, about 5 to about 500 mg N-(mercaptoalkyl)urea or carbamate per dose given 1 to 4 times a day and about 0.01 to about 1 mg ANF given 1 to 6 times a day (total daily dosage range of 5 to 2000 mg day and .01 to 6 mg/day, respectively); and for the combination of an N-(mercaptoalkyl)urea or carbamate and an ACE inhibitor, about 5 to about 500 mg N-(mercaptoalkyl)urea or carbamate per dose given 1 to 4 times a day and about 5 to about 50
  • compounds of this invention will be administered in a dosage range of from about 1 to about 100 mg/kg.
  • the doses are to be administered at intervals of from 3 to 8 hours.
  • the quantity and frequency of dosage will depend upon such factors as the severity of the pain, the general physical condition of the patient, the age and weight of the patient, and other factors recognized by the skilled clinician.
  • dosage ranges of the compounds of this invention are the same as for treatment of hypertension with the use of N-(mercaptoalkyl)ureas or carbamates alone or in combination with ANF.
  • Typical oral formulations include tablets, capsules, syrups, elixirs and suspensions.
  • Typical injectable formulations include solutions and suspensions.
  • the typical acceptable pharmaceutical carriers for use in the formulations described above are exemplified by: sugars such as lactose, sucrose, mannitol and sorbitol, starches such as cornstarch, tapioca starch and potato starch; cellulose and derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose; calcium phosphates such as dicalcium phosphate and tricalcium phosphate; sodium sulfate; calcium sulfate; polyvinylpyrrolidone, polyvinyl alcohol; stearic acid; alkaline earth metal stearates such as magnesium stearate and calcium stearate, stearic acid, vegetable oils such as peanut oil, cottonseed oil, sesame oil, olive oil and corn oil; non-ionic, cationic and anionic surfactants; ethylene gylcol polymers; beta-cyclodextrin; fatty alcohols and hydrolyzed cereal solids; as well as other nontoxic
  • kits are contemplated, each combining two separate units: an N-(mercaptoalkyl)urea or carbamate pharmaceutical composition and an ANF pharmaceutical composition in one kit and an N-(mercaptoalkyl)urea or carbamate pharmaceutical composition and an ACE inhibitor pharmaceutical composition in a second kit.
  • kit form is particularly advantageous when the separate components must be administered in different dosage forms (e.g. oral and parenteral) or are administered at different dosage intervals.
  • the term "active ingredient” designates a compound of formula I or II, preferably N1-[1(R)-acetylthio-3-(2-methylphenyl)-2-propyl]-N3-(ethoxycarbonylmethyl)urea or carboxymethyl N-[1(R)-mercapto-3-(2-methylphenyl)-2-propyl]carbamate.
  • active ingredient designates a compound of formula I or II, preferably N1-[1(R)-acetylthio-3-(2-methylphenyl)-2-propyl]-N3-(ethoxycarbonylmethyl)urea or carboxymethyl N-[1(R)-mercapto-3-(2-methylphenyl)-2-propyl]carbamate.
  • these compounds can be replaced by equally effective amounts of other compounds of formula I or II.

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Claims (19)

  1. Composé ayant la formule de structure
    Figure imgb0056
        ou
    Figure imgb0057
     où :
       A est un arylène ou hétéroarylène monocyclique ou bicyclique;
       Q est hydrogène ou R₉CO-;
       Y est -O-,-S- ou -NR₈-;
       R₁ est alkyle inférieur, cycloalkyle inférieur, aryle ou hétéroaryle;
       R₂ et R₈ sont indépendamment hydrogène; alkyle inférieur; cycloalkyle inférieur; alkyle inférieur substitué par hydroxy, alcoxy inférieur, mercapto, alkylthio inférieur, aryle ou hétéroaryle, aryle ou hétéroaryle;
       R₃ est -OR₅ ou -NR₅R₆;
       R₄ est -(CH₂)qR₇; ou R₂ et R₄ et les carbones auxquels ils sont attachés forment un noyau carbocyclique de 5, 6 ou 7 membres;
       R₅ et R₆ sont indépendamment choisis dans le groupe consistant en hydrogène, alkyle inférieur, hydroxy alkyle inférieur, alcoxy inférieur alkyle inférieur et aryl alkyle inférieur, ou bien R₅ et R₆ avec l'azote auquel ils sont attachés, forment un noyau de 5, 6 ou 7 membres où R₅ et R₆ forment ensemble une chaîne d'alkylène C₄ à C₆;
       R₇ est hydrogène, hydroxy, alcoxy inférieur, alkanoyloxy inférieur, mercapto, alkylthio inférieur, aryle ou hétéroaryle;
       R₉ est hydrogène, alkyle inférieur ou aryle;
       m est 1 ou 2;
       n est 0, 1 ou 2;
       p est 0 ou 1; et
       q est 0, 1 ou 2;
    ou bien un sel acceptable en pharmacie.
  2. Composé de la revendication 1, où R₁ est phényle ou phényle substitué par alkyle inférieur et m est 1.
  3. Composé selon l'une quelconque des revendications 1 ou 2 où R₃ est hydroxy ou alcoxy inférieur.
  4. Composé selon l'une quelconque des revendications 1, 2 ou 3 où Y est -O- ou -NR₈- et R₈ est hydrogène, alkyle ou phényle.
  5. Composé selon l'une quelconque des revendications 1, 2, 3 ou 4 où p est zéro.
  6. Composé selon l'une quelconque des revendications 1, 2, 3, 4 ou 5 où R₂ est hydrogène ou phényle.
  7. Composé selon la revendication 1 ayant la formule de structure
    Figure imgb0058
     où m est 1, R₁ est 2-méthylphényle et p est zéro, et où Q, Y, R₂, n et R₃ ont les valeurs qui suivent : Q Y R₂ n R₃ Ac -NH- H 0 OEt H -NH- H 0 OH Ac -N(CH₃)- H 0 OEt Ac -N(CH₃)- H 0 O-t-Bu Ac -N(CH₃)- H 0 OH H -N(CH₃)- H 0 OH Ac -N(C₆H₅)- H 0 OEt Ac -N(C₆H₅)- H 0 O-t-Bu Ac -N(C₆H₅)- H 0 OH H -N(C₆H₅)- H 0 OH Ac -NH- H 1 O-Benzyl H -NH- H 1 OH Ac -S- H 0 OEt Ac -S- H 0 OH Ac -O- H 0 OEt H -O- H 0 OH Ac -O- -C₆H₅ 0 OMe H -O- -C₆H₅ 0 OH
    où Et est éthyle, Me est méthyle, Bu est butyle et Ac est acétyle.
  8. Composé selon l'une quelconque des revendications 1, 2, 3 ou 4 où A est phénylène.
  9. Composé selon la revendication 1 ayant la formule de structure
    Figure imgb0059
     où m est 1, R₁ est 2-méthylphényle, A est 4-phényléne et où Q, Y et R₃ ont les valeurs suivantes : Q Y R3 Ac -NH- OEt H -NH- OEt H -NH- OH Ac -O- OMe Ac -O- OH
    ou Et est éthyle, Me est méthyle et Ac est acétyle.
  10. Composé de la revendication 1, seul ou en association avec un facteur natriurétique atrial ou un inhibiteur de l'enzyme de conversion de l'angiotensine, à utiliser dans une méthode pour le traitement de l'hypertension, de l'asystolie congestive, de l'oedème, de l'insuffisance reinale, de la nephrotoxicité ou de la douleur chez les mammifères.
  11. Composition pharmaceutique pour le traitement de l'hypertension, de l'asystolie congestive, de l'oedème, de l'insuffisance reinale, de la néphrotoxicité ou de la douleur chez les mammifères comprenant une quantité efficace d'un composé de la revendication 1, seul ou en association avec un facteur atrial natriurétique ou un inhibiteur de l'enzyme de conversion de l'angiotensine dans un support pharmaceutiquement acceptable.
  12. Composition de la revendication 11, où le peptide atrial natriurétique est choisi parmi AP 21 α humain, AP 28 α humain, AP 23 α humain, AP 24 α humain, AP 25 α humain, AP 26 α humain, AP 33 α humain, et les peptides atriaux correspondants, où la méthionine à la position 12 est remplacée par l'isoleucine.
  13. Composition de la revendication 11, où l'inhibiteur de l'enzyme de conversion de l'angiotensine est choisi parmi:spirapil, énalapril, ramipril, périndopril, indolapril, lysinopril, quinapril, pentopril, cilazapril, captopril, zofénopril, pivalopril et fosinopril.
  14. Trousse comprenant, dans des conteneurs séparés dans un seul paquet, des compositions pharmaceutiques à utiliser en association pour traiter l'hypertension, l'asystolie congestive ou la néphrotoxicité chez les mammifères qui comprend, dans un conteneur, une composition pharmaceutique comprenant une N-(mercaptoakyl)urée ou un carbamate de la revendication 1 et, dans un second conteneur, une composition pharmaceutique comprenant un facteur atrial natriurétique.
  15. Trousse comprenant, dans des conteneurs séparés dans un seul paquet, des compositions pharmaceutiques à utiliser en association pour traiter l'hypertension ou l'asystolie congestive chez les mammifères, qui comprend, dans un conteneur, une composition pharmaceutique comprenant une N-(mercaptoalkyl)urée ou un carbamate de la revendication 1, et dans un second conteneur, une composition pharmaceutique comprenant un inhibiteur de l'enzyme de conversion de l'angiotensine.
  16. Utilisation d'un composé de la revendication 1 pour la fabrication d'un médicament pour le traitement de l'hypertension, de l'asystolie congestive, de l'oedème, de l'insuffisance reinale, de la néphrotoxicité ou de la douleur.
  17. Méthode de préparation d'une composition pharmaceutique comprenant le mélange d'un composé de la revendication 1 avec un support acceptable en pharmacie.
  18. Composition pharmaceutique selon l'une quelconque des revendications 11, 12 et 13, ladite composition étant en forme de dosage.
  19. Procédé pour la préparation de composés de formule I et II selon la revendication 1, où Q, A, R₁, R₂, R₃, R₄, Y, m, n et p sont tels que définis à la revendication 1, comprenant une protection appropriée, choisi parmi les procédés, A, B, C et D qui suivent :
       Procédé A pour la préparation de composés de formule I qui comprend la réaction d'un isocyanate de formule IV avec une amine, un alcool ou un thiol de formule V
    Figure imgb0060
     avec ensuite isolement de l'isomère préféré, si on le souhaite, et enlèvement des groupes protecteurs, si nécessaire, pour donner le produit souhaité et, si on le souhaite, la préparation de son sel;
       Procédé B pour la préparation de composés de formule I qui comprend la réaction d'un isocyanate de formule VI avec une amine, un alcool ou un thiol de formule VI
    Figure imgb0061
     avec ensuite isolement de l'isomère préféré, si on le souhaite et enlèvement des groupes protecteurs, si nécessaire, pour donner le produit souhaité et si, on le souhaite, la préparation de son sel.
       Procédé C pour la préparation de composés de formule I, où Y est -NH-, -NR₈-, ou -O-, qui comprend la réaction d'une amine VIII ou de son dérivé réactif ayant un composé de formule IX
    Figure imgb0062
     où Z est -NCO, -N(R₈)COCl, ou -OC(O)Cl, avec ensuite isolement de l'isomère préféré, si on le souhaite, et enlèvement des groupes protecteurs, si nécessaire, pour donner le produit souhaité et, si on le souhaite, la préparation de son sel;
       Procédé D pour la préparation d'un composé de formule II, où Y est -NH-, -NR₈-, et -O-, qui comprend la réaction d'une amine VIII ou de son dérivé réactif avec un composé de formule X
    Figure imgb0063
     où Z est -NCO, -N(R₈)COCl, ou -OC(O)Cl, avec ensuite isolement de l'isomère préféré, si on le souhaite, et enlèvement des groupes protecteurs, si nécessaire, pour donner le produit souhaité et, si on le souhaite, la préparation de son sel.
EP91914916A 1990-08-16 1991-08-14 N-(mercaptoakyl)urees et carbamates Expired - Lifetime EP0543892B1 (fr)

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US568569 1990-08-16
US07/568,569 US5173506A (en) 1990-08-16 1990-08-16 N-(mercaptoalkyl)ureas and carbamates
PCT/US1991/005587 WO1992003410A1 (fr) 1990-08-16 1991-08-14 N-(mercaptoakyl)urees et carbamates

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US5173506A (en) 1992-12-22
US5356925A (en) 1994-10-18
DE69105274D1 (en) 1995-01-05
ATE114301T1 (de) 1994-12-15
WO1992003410A1 (fr) 1992-03-05
DE69105274T2 (de) 1995-05-04
EP0543892A1 (fr) 1993-06-02
AU8445591A (en) 1992-03-17

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